Overexpression of inducible cyclic AMP early repressor inhibits transactivation of genes and cell proliferation in pancreatic β cells
Overexpression of inducible cyclic AMP early repressor inhibits transactivation of genes and cell proliferation in pancreatic β cells
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DOI：
10.1128/mcb.24.7.2831-2841.2004
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发表时间：
2004-04-01
影响因子：
5.3
通讯作者：
Seino, Y
中科院分区：
文献类型：
--
作者：
Inada, A;Hamamoto, Y;Seino, Y
环AMP-responsive element （CRE）介导的转录调控是基因调控的重要机制。为了验证我们的假设，即增加的诱导环AMP早期抑制因子（ICER） Igamma抑制cre结合蛋白的功能，从而破坏cre介导的胰腺β细胞转录，我们产生了具有β细胞定向表达ICER Igamma的转基因小鼠，ICER Igamma是一种强大的抑制因子，在糖尿病中大大增加。三个转基因细胞系清楚地表明，β细胞中ICER Igamma表达增加导致早期严重糖尿病。从出生开始，胰岛就严重紊乱，整个胰岛的et细胞比例显著增加。糖尿病是胰岛素表达受损和β细胞数量减少共同作用的结果。β细胞的减少似乎是由于出生后增殖受损而不是由于细胞凋亡增加。Cyclin A基因表达因ICER的强抑制而受损；细胞周期蛋白A的抑制导致出生后β细胞的增殖显著减少。这些结果表明，CRE和CRE结合因子不仅通过直接调控基因反式激活，还通过间接调控β细胞质量，在胰腺β细胞生理中发挥重要作用。
Transcriptional control mediated by the cyclic AMP-responsive element (CRE) represents-an important mechanism of gene regulation. To test our hypothesis that increased inducible cyclic AMP early repressor (ICER) Igamma inhibits function of CRE-binding proteins and thus disrupts CRE-mediated transcription in pancreatic beta cells, we generated transgenic mice with beta-cell-directed expression of ICER Igamma, a powerful repressor that is greatly increased in diabetes. Three transgenic lines clearly show that increased ICER Igamma expression in beta cells results in early severe diabetes. From birth islets were severely disorganized with a significantly increased proportion of et cells throughout the islet. Diabetes results from the combined effects of impaired insulin expression and a decreased number of beta cells. The decrease in beta cells appears to result from impaired proliferation rather than from increased apoptosis after birth. Cyclin A gene expression is impaired by the strong inhibition of ICER; the suppression of cyclin A results in a substantially decreased proliferation of beta cells in the postnatal period. These results suggest that CRE and CRE-binding factors have an important role in pancreatic beta-cell physiology not only directly by regulation of gene trans-activation but also indirectly by regulation of beta-cell mass.